Scheduling of anticancer drugs

Abstract

Many cancer patients are treated with a combination of anticancer drugs. Here, we discuss the importance of drug scheduling and the need for studies that investigate the optimal timing of the various anticancer drugs. Positron emission tomography (PET) using radiolabeled anticancer drugs could be an important tool for those studies.

Introduction

Over the past decades, the development of new drugs and new treatment modalities has improved the prospect of cancer patients. To date, numerous drugs have been introduced. This number is still increasing, and an ever increasing number of drugs will become available for the treatment of cancer. A new anticancer drug is often added to an existing treatment strategy, as combination therapies reduce the development of drug resistance, leading to synergy^1,2 and a lower rate of treatment failure. As a result, an increasing number of combination therapies are under investigation for clinical implementation. Usually, the feasibility of new combination strategies is evaluated in phase-I, phase-II and eventually in phase-III trials. The purpose of phase-I studies is to assess whether patients can tolerate a new combination of anticancer drugs, and therefore both incidence and severity of experienced adverse events are scored. In addition, pharmacokinetic analyses are performed to determine the effects of combination strategies on plasma levels of the drugs and their metabolites. In a phase-II trial, the new combination can be investigated in specific cancer types. Furthermore, it is evaluated whether it is feasible to test the new combination in a larger phase-III trial. When the new combination successfully passes phase-I and phase-II trials, it finally reaches a phase-III trial. In these phase-III trials, the additional value of the new drug is compared with standard therapy. In a phase-III trial, patients are randomized to a treatment with or without the new drug, and the clinical outcomes of the two arms, usually defined as overall survival, are compared. Based on positive results of a randomized phase-III trial, the new drug can be registered and find its way to the clinic. Within the context of a new combination, however, optimal scheduling of drugs often is not investigated. In this perspective, we will discuss whether scheduling of anticancer drugs may affect efficacy of anticancer treatment. In addition, we will illustrate how positron emission tomography (PET) using radiolabeled anticancer drugs may be an important method to elucidate the importance of drug scheduling.

Anti-Angiogenic Drugs for Treatment of Cancer

Among approved anticancer agents, drugs that target tumor angiogenesis are currently widely prescribed for the treatment of several advanced malignancies.^3-9 Angiogenesis is essential for survival of malignant tumors^10,11 and has become an important target in the treatment of cancer. In particular, drugs have been developed that target pathways of the vascular endothelial growth factor (VEGF) and its receptors (VEGFR).¹² VEGF is overexpressed in malignant tumors, and it is an important growth factor for tumor angiogenesis.¹³ As single-agents, however, anti-angiogenic drugs usually are not sufficiently effective for the treatment of most malignancies. Consequently, anti-angiogenic drugs often are combined with conventional chemotherapy, as this strategy has shown additional value in several cancers.^3,4,7 However, the story of the anti-angiogenic drug bevacizumab has shown that the place of anti-angiogenic drugs in the clinic is not certain, as an initially obtained approval can, in case of disappointing results, be revoked by the Food and Drug Administration (FDA). In 2008, bevacizumab, a humanized monoclonal antibody that targets circulating VEGF,¹⁴ was granted accelerated approval for first-line treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer.^5,15 At the time, addition of bevacizumab to paclitaxel was approved on the basis of a significant improvement in progression-free survival as compared with paclitaxel alone.^5,15 Later studies, however, could not confirm the increase in progression-free survival, which is a surrogate clinical end point, and did not show evidence for improved overall survival.¹⁶ As a result, the FDA concluded that bevacizumab was not shown to be effective in patients with (HER2)-negative metastatic breast cancer, and its approval for this patient population was revoked.¹⁶ It has been suggested that the discrepant results for bevacizumab in the treatment of metastatic breast cancer may be explained by the different chemotherapy regimens used and that the additional value of bevacizumab may be chemotherapy-specific.¹⁷ More importantly, scheduling of anticancer drugs may also affect the delivery of chemotherapy to tumors, potentially leading to differences in efficacy of combination therapy. In the latter case, PET using radiolabeled anticancer drugs can be used to investigate this potential mechanism.

PET Using Radiolabeled Anticancer Drugs

In oncology, PET scans using fluorine-18-labeled deoxy-glucose [2-(¹⁸F)fluoro-2-deoxy-D-glucose or (¹⁸F)FDG] are used routinely for diagnosis and staging of numerous malignancies.¹⁸ In addition, this non-invasive imaging technique can also be applied to monitor pharmacokinetics and pharmacodynamics of anticancer drugs in vivo.¹⁹ To this end, a tracer dose (microdose) of an anticancer drug is radiolabeled with a short-lived positron emitting radionuclide such as carbon-11 or fluorine-18. After intravenous administration of a radiolabeled anticancer drug, its uptake in tumor tissue can be measured non-invasively using PET. Preliminary PET studies using fluorine-18-labeled 5-fluorouracil [(¹⁸F)5-FU],^20,21 fluorine-18-labeled tamoxifen [(¹⁸F)fluorotamoxifen]²² and carbon-11-labeled docetaxel [(¹¹C)docetaxel]²³ have demonstrated that high tumor uptake of the radiolabeled anticancer drug was associated with improved tumor response. These studies indicate that radiolabeled anticancer drugs may be useful for predicting outcome prior to start of treatment. In addition, such PET scans can be useful to investigate whether tumor uptake of a radiolabeled drug is affected by administration of another drug.

Role of PET for Evaluation of Drug Scheduling

The effects of drug scheduling can be explored using PET and radiolabeled anticancer drugs. On one hand, PET using radiolabeled drugs can contribute to conventional pharmacokinetic studies by monitoring metabolism of the radiolabeled drug. For example, administration of eniluracil, an inhibitor that suppresses catabolism of 5-FU by inactivating dihydrouracil dehydrogenase in the liver, decreased (¹⁸F)5-FU uptake in normal liver and kidneys, increased plasma levels of uracil and non-metabolized (¹⁸F)5-FU and improved uptake of radioactivity in tumors, reflecting enhanced tumor uptake of (¹⁸F)5-FU and/or its radiolabeled anabolites.^24-27 On the other hand, effects of other (anticancer) drugs on the delivery of radiolabeled drugs to tumors can be evaluated. Several PET studies have applied this concept to (¹⁸F)5-FU.^28,29 It has been shown that interferon-α increases perfusion and uptake of (¹⁸F)5-FU in several malignant tumors, whereas N-phosphonacetyl-L-aspartate (PALA) induces a decrease in these parameters.²⁹ As drug delivery to tumors may be related to tumor perfusion,²³ administration of drugs that affect tumor perfusion is of interest.^30,31 Tumor perfusion can be assessed using PET and radioactive water [(¹⁵O)H₂O], which has a half-life of ~2 min, enabling sequential PET scans using both (¹⁵O)H₂O and a radiolabeled anticancer drug.³² For example, (¹⁵O)H₂O PET showed that administration of angiotensin II, a drug that causes hypertension, selectively increases perfusion in hepatic tumors.^33-35 As mentioned above, effects of anti-angiogenic drugs on drug delivery to tumors is of special interest. Recently, we have investigated the effect of bevacizumab on delivery of (¹¹C)docetaxel to tumors.³⁶ Non-small cell lung cancer patients underwent PET scans with (¹⁵O)H₂O and (¹¹C)docetaxel prior to and at 5 h and 4 d after infusion of bevacizumab. Within 5 h, both perfusion and (¹¹C)docetaxel uptake in tumors had significantly decreased, and these effects persisted after 4 d. Reduction in (¹¹C)docetaxel delivery to tumors was accompanied by rapid reduction in circulating levels of VEGF, but was not associated with changes in cardiovascular parameters, including blood pressure, cardiac output and capillary density in the skin. According to these results, a 20% decline in (¹⁸F)5-FU uptake was also measured in human colorectal cancer at 24 h after administration of bevacizumab.³⁷ Besides a decrease in drug delivery (Fig. 1A and B), the decreased tumor perfusion results in oxygen deficiency (also called hypoxia) in tumors, which, in turn, may result in more aggressive cancer cell populations that have an increased capacity to spread to other organs (Fig. 1C).^38,39 Although the mentioned PET studies do not prove that the bevacizumab-induced reduction in delivery of chemotherapy affects efficacy of the drugs, they highlight the importance of drug scheduling⁴⁰ and show that the administration of anti-angiogenic drugs may be considered after the cytotoxic drugs, as the immediate decrease in tumor perfusion may decrease clearance of cytotoxic drugs from tumor tissue. In addition, these studies show the promising application of radiolabeled anticancer drugs for characterizing the effects of drug scheduling on their delivery to tumors, in particular, that of anti-angiogenic drugs. Apart from the applications mentioned above, effects of inhibitors of efflux transporters, such as ABCB1, are also of interest. Overexpression of ABCB1 is found in many drug-resistant tumors⁴¹ and may decrease drug uptake in tumors. Consequently, inhibitors of ABCB1 may improve drug uptake in tumors. In addition, inhibitors of ABCB1 may decrease the rapid clearance of drugs from blood,^42,43 as ABCB1 is also extensively expressed in intestine and the biliary system,⁴⁴ and may contribute to drug elimination.⁴⁵ Therefore, PET studies using both radiolabeled anticancer drugs and tracers that can show in vivo functionality of multidrug resistance (MDR) transporters [e.g., (R)-(¹¹C)verapamil] may provide more insight into the role of MDR in (lack of) drug uptake by tumors.

Figure 1. (A) Several cancers are treated with anti-angiogenic drugs, either alone or in combination with cytotoxic agents that inhibit the growth of cancer cells. Some of these cancer cells (green) are particularly dangerous, because they can be more resistant to cytotoxic therapy than the other cancer cells. These dangerous cells can easily spread to other organs to seed new tumors. A decreased blood supply to the tumor, which is the main benefit from anti-angiogenic therapy, (B) can reduce the distribution of cytotoxic drugs in the tumor,³⁶ potentially affecting their efficacy. In addition, a decreased blood supply (C) can reduce oxygen levels in the tumor, leading to the accumulation of more aggressive cells that have an increased capacity to spread to other organs.³⁸ Figure reproduced with permission from reference.⁴⁰

Clinical Application of PET for Drug Scheduling

Prior to clinical application of a radiolabeled anticancer drug, PET measurements should be validated and their reproducibility determined. The development of radiolabeled anticancer drugs is very expensive and time-consuming,^46,47 as a complex and expensive research infrastructure as well as highly qualified personnel are required. Because of the complexity and high costs of PET scans using radiolabeled anticancer drugs, at present they cannot be applied on a large scale. Nevertheless, PET using radiolabeled anticancer drugs may be useful to evaluate the effects of drug scheduling, and they may help to design large clinical studies that will investigate effects of scheduling and sequence on drug efficacy in cancer patients. Ultimately, a clinical trial is needed in which cancer patients are randomized to different administration schedules. Until then, observational data may be useful to reveal whether drug scheduling affects efficacy of combination therapy. In clinical trials, careful registration of the administration sequence may help to explain the failure of a specific combination. Although such a registration appears to be rather simple, it can be difficult to maintain a particular drug sequence in clinical practice, as scheduling and sequence of drugs may be determined by practical and logistical issues such as delivery of drugs by the pharmacy or the (potential) risk for acute allergic reactions during infusion. Hence, there is a need for study protocols that define both sequence and timing of administration of the various drugs.⁴⁸

Conclusions

To date, cancer patients frequently are treated with a combination of anticancer drugs, as this strategy often results in an improved efficacy. Optimal scheduling of combination therapies, however, is not known, and the role of drug scheduling seems to be underexposed.⁴⁹ PET using radiolabeled drugs is a promising method to evaluate effects of drug scheduling. In particular, this imaging technique may help to define the optimal design of large clinical studies to investigate the effects of scheduling on efficacy in cancer patients. To gain more insight into scheduling as a potential contributing factor of efficacy, both sequence of and interval between anticancer drugs should be clearly defined. Future studies should be focused on optimal scheduling of anticancer drugs in order to improve the efficacy of combination therapies for cancer patients.